The blood brain barrier (BBB) is a system-wide membrane barrier that prevents the brain uptake of circulating drugs, protein therapeutics, RNAi drugs, and gene medicines. Drugs or genes can be delivered to the human brain for the treatment of serious brain disease either (a) by injecting the drug or gene directly into the brain, thus bypassing the BBB, or (b) by injecting the drug or gene into the bloodstream so that the drug or gene enters the brain via the transvascular route across the BBB. With intra-cerebral administration of the drug, it is necessary to drill a hole in the head and perform a procedure called craniotomy. In addition to being expensive and highly invasive, this craniotomy based drug delivery to the brain approach is ineffective, because the drug or gene is only delivered to a tiny volume of the brain at the tip of the injection needle. The only way the drug or gene can be distributed widely in the brain is the transvascular route following injection into the bloodstream. However, this latter approach requires the ability to undergo transport across the BBB. The BBB has proven to be a very difficult and stubborn barrier to traverse safely.
The traditional approach to delivery of drugs across the BBB is called “BBB disruption”. One of the earliest techniques tried is the transient disruption of the barrier (BBBD) by infusing hyperosmolar solutions, which sucks water out of capillary endothelial cells, thereby shrinking them to open the gaps [47-49]. Another approach to disrupt BBB is the use of bradykinin receptor agonists, such as the compound RMP7 (Cereport, Alkermes), which binds to the receptors on the surface of endothelial cells and kicks off a biochemical cascade that loosens the tight junctions [50]. However, none of these methods is very effective and moreover, they suffer from the drawback that BBB disruption also allows the non-specific entry of other potentially brain-toxic molecules such as serum albumin. Accordingly, this approach has not gained widespread clinical acceptance.
Transvascular approach provides the most ideal noninvasive means to treat neurological diseases. If not for the BBB, the capillaries, which stretch for over 400 miles in the brain and encase virtually every brain cell, would offer the most promising delivery approach [46]. The most promising transvascular approach to brain is to use transporter molecules since this allows delivery of specific molecules without disrupting the BBB [46]. A peptidomimetic mAb, such as against the transferrin receptor can be used as a molecular “Trojan horse” to ferry any attached drug or gene across the BBB. Recently, great progress has been made in brain delivery by combining the antibody targeting technology with siRNA encapsulation within liposomes [46]. The problems associated with the use of conventional cationic polyplexes, such as the aggregation of the DNA and sequestration in the lung and liver can be eliminated if the DNA is encapsulated in the interior of a nanocontainer such as a liposome or a polymeric nanoparticle. If the surface of the liposome is conjugated with polyethylene glycol or hyaluron, this makes the liposome stable in blood with prolonged blood residence times. If the tips of PEG or hyaluron are conjugated with a BBB molecular “Trojan horse”, such as anti-transferrin receptor antibody, this immunoliposome is effectively delivered across the BBB. This system has been used to deliver reporter genes with success in the rat, mice and monkey brains [76-81]. Recently, this technology has also been used to deliver shRNAs to target specific genes in brain tumors in mice as well as monkeys [37,82]. Thus, this method seems optimal to introduce shRNA encoding vectors as well as synthetic siRNA duplexes.